Part 4

Stovaine, or benzoyl-ethyl-dimethylaminopropanol hydrochloride, more recently introduced, is a synthetic product elaborated by Fourneau, and derived from tertiary amyl alcohol. It is much less toxic than cocaine, but its comparative value still remains to be proved by further trial. Tropa-cocaine, a drug closely allied to cocaine, and derived from the leaves of the Java coca plant, has recently been much used in Germany, but it does not appear to possess any advantages over cocaine or eucaine.

Novocaine, or para-amido-benzoyl-diethylamino-ethenol hydrochloride, has lately been found to possess satisfactory properties as a local anæsthetic in dental operations. It is said to be free from the toxic and local irritant action common to other local anæsthetics.

THE NECESSITY FOR ABSOLUTE PURITY IN CHLOROFORM

[Sidenote: Administration of Chloroform]

[Sidenote: Purity an essential]

[Sidenote: Danger of impurities]

Considerable attention has been directed to different methods of administering chloroform, and various forms of apparatus have been devised which claim to reduce to a minimum the dangers of anæsthesia. Assuming a most skilled and competent administrator, an ideal method of administration, and a suitable patient, an unsatisfactory result can only be attributed to the chloroform employed. Purity of chloroform is a most important factor in contributing to safe anæsthesia. The physician claims that absolute purity shall characterise all medicinal agents, and the justice of the claim is acknowledged by the trend of recent legislation. Purity is a prime essential of any anæsthetic. The presence of impurities largely increases the risk inseparable from the use of chloroform. The train of symptoms observed during the normal process of anæsthesia may be masked and altered, and dangerous results may supervene under the most competent, careful and observant administrator.

[Illustration: AN OPERATION IN THE TWENTIETH CENTURY]

[Sidenote: Expert testimony]

That some of the chloroform offered to the profession may reasonably be regarded with suspicion is evidenced by the words of a prominent obstetrician, based on the experience of 40 years in the use of chloroform; this authority expresses himself as follows: “I may say I fear the chloroform in common use is often far from being as pure as it should be, and is sometimes very defective in this respect.”

[Sidenote: Effects of impurities]

Impurities may result from the process of manufacture, or from decomposition. Conspicuous amongst these undesirable elements are chlorine, hydrochloric acid and carbonyl chloride (phosgene), which irritate the lining membrane of the respiratory tract and interfere with the normal process of respiration. Such irritation may result in arrest of cardiac action or may produce a severe form of bronchitis. It is obviously of great importance that chloroform should be free from irritating properties, that the respiratory passages should not be obstructed, and that during anæsthesia the breathing and the circulation should approximate the normal. Superadded to these results, produced by local irritation, is the effect of other impurities which exert their action after absorption. These latter markedly increase the cardiac depression which has been shown to follow the administration of pure chloroform. Such an action is difficult of detection, and is, probably, in large degree responsible for a considerable number of the accidents reported.

[Sidenote: Contradictory results]

[Sidenote: Recent research]

[Sidenote: Ethyl chloride]

Of recent years increased knowledge has elaborated exact tests, which ensure the absence of these impurities. Nevertheless, anæsthetists of wide experience have obtained results which could not be reconciled with the use of pure chloroform. It has been observed that different chloroforms, all of which answer the official tests for purity, give effects which are difficult to harmonise, and the interpretation of which only appears satisfactory on the assumption that the chloroforms differ in composition. Whilst one chloroform acts most satisfactorily, another produces, during the early stages of administration, a marked excitement and an irregularity of breathing, which prolongs the period of induction. Further investigation has therefore been deemed necessary, and a comprehensive and careful research has elucidated the cause of these hitherto unexplained phenomena (Wade and Finnemore, “Journal of the Chemical Society,” 1904, 85, 938). In the chloroforms which produced anæsthesia in a satisfactory manner, has been demonstrated the presence of ethyl chloride in minute and varying quantities. When the undesirable effects were noted, no ethyl chloride was detected in the anæsthetic. A physiological test conclusively proved that ethyl chloride was the factor which determined these differences.

[Sidenote: Value of the investigation]

A chloroform which had previously given undesirable effects, and in which the presence of ethyl chloride could not be demonstrated, was modified so as to contain a small proportion of the latter. The chloroform then proved a most satisfactory anæsthetic, and there was entire absence of the excitement and respiratory irregularity previously observed. The results of this research are of the utmost value. In the initial stages of the induction of chloroform anæsthesia, the presence of a small quantity of ethyl chloride has a beneficial effect, leading to the absence of mental excitement, and steadies the breathing. The respiration is stimulated and becomes regular and deep. In these circumstances, satisfactory anæsthesia is induced with rapidity and ease.

A CHRONOLOGICAL TABLE OF CHIEF EVENTS AND DISCOVERIES IN THE HISTORY OF ANÆSTHESIA

NITROUS OXIDE

Joseph Priestley 1776 Humphry Davy 1800 Horace Wells (Colton, Riggs, Evans, Best) 1844

ALCOHOL

Collier 1835–42

ETHER

Michael Faraday 1818 W. E. Clarke 1839 Crawford W. Long 1842 E. E. Marcy 1844 W. T. G. Morton 1846 Charles T. Jackson 1846 First surgical operation in America October 16, 1846 First surgical operation in Great Britain December 21, 1846

(Warren, Hayward, Bigelow, Boote, Robinson, Liston, Buchanan, Louget, Snow, Simpson, Bernard, Clover)

CHLOROFORM

Guthrie 1831 Waldie 1847 James Young Simpson 1847 First surgical operation under chloroform, in Edinburgh November 15, 1847

(Soubeiran, Liebig, Dumas, Flourens, M. Duncan, G. Keith, Snow, Nunneley, James Arnott)

COCAINE

Gädeke 1855 Hughes Bennett 1874 Von Anrep 1880 Koller 1884

[Illustration: ‘Wellcome’ Brand Chloroform, 1/4 lb. in drop bottle--exact size]

‘WELLCOME’ BRAND CHLOROFORM

[Sidenote: Ethyl chloride]

[Sidenote: Conforms to B.P.]

‘Wellcome’ Brand Chloroform represents the results of the most recent researches. It embodies the essentials of purity and uniformity, the necessary basis of a satisfactory chloroform. Some chloroforms which satisfy official standards have yet been shown to vary in composition and in effect, the result depending on the occurrence in the preparation of a small and varying quantity of ethyl chloride. ‘Wellcome’ Brand Chloroform is of constant composition and gives uniform effects. It conforms in every respect to the requirements of the B.P., and contains a small and definite proportion of ethyl chloride, which has been found to assist the satisfactory induction of anæsthesia.

[Illustration: ‘Wellcome’ Brand Chloroform, 30 c.c., in hermetically-sealed tube. Length of tube, 5-1/4 in.]

[Sidenote: Proved value]

[Sidenote: Confidence in administration]

‘Wellcome’ Brand Chloroform is the result of prolonged laboratory experiment and careful clinical observation. Its reception by the profession verifies the theory upon which its production is based. It has been largely used in hospital and in private practice, and with gratifying results. Reports from most experienced anæsthetists agree in regarding ‘Wellcome’ Brand Chloroform as a distinct advance. Its constancy in composition gives confidence in administration, and its freedom from irritating and depressant principles removes the source of many of the accidents which have hitherto been regarded as grave objections to the employment of chloroform as an anæsthetic.

‘Wellcome’ Brand Chloroform is issued in 2 oz., 1/4 lb., 1/2 lb. and 1 lb. amber-coloured bottles; also in 30 c.c. and 60 c.c. hermetically-sealed tubes, as illustrated on the previous page.

‘WELLCOME’ BRAND ETHER

‘Wellcome’ Brand Ether is prepared specially for anæsthesia and is thoroughly pure and reliable. When the administration of ether is desired, this product will be found eminently suitable.

[Sidenote: Ideal packing]

The method of packing in hermetically-sealed tubes is especially desirable with such a volatile substance as ether, and the shape of the glass tube admits of the contents being readily transferred to the graduated bottles usually employed.

[Sidenote: Conforms to B.P.]

‘Wellcome’ Brand Ether conforms to the requirements of the British Pharmacopœia for _Æther Purificatus_, and has a specific gravity of 0·720.

‘Wellcome’ Brand Ether is issued in hermetically-sealed tubes containing 30 c.c. and 60 c.c., similar to the Chloroform packing illustrated on the previous page.

The anæsthetics issued under the ‘Wellcome’ Brand denote the highest degree of perfection and purity.

‘WELLCOME’ BRAND PRODUCTS

It is well known that considerable variation exists in the quality and activity of the medicinal chemicals of commerce.

[Sidenote: The need for reliable Medicinal Chemicals]

Purity and reliability are matters of the utmost importance to prescriber, dispenser and patient alike, and every opportunity should therefore be taken to ensure the supply of only those chemicals and galenicals which are known to be thoroughly pure and trustworthy.

In order that goods answering to this description in the highest sense may be at the disposal of the profession, Burroughs Wellcome & Co. manufacture and issue a series of fine chemicals, alkaloids, etc., to which they have recently added a series of standardised liquid and granular extracts and concentrated tinctures, under the distinctive title of the ‘Wellcome’ Brand.

[Sidenote: Standardised galenicals]

[Sidenote: Physiological standards]

The advantages of galenicals containing a definite proportion of active principle over those that vary in strength with every sample of drug employed are now fully recognised, and several such have been admitted into the Pharmacopœia. With regard to galenicals, Burroughs Wellcome & Co. have extended the standardisation by total alkaloid assay, and have never adopted the basis of total extractive, regarding it as misleading and useless. Total alkaloid estimations have been adopted in so far as they secured definite standards of truly representative activity, but the firm has not been content to rely on this means alone. As the result of extensive research, they are able to offer many other standardised preparations in addition to the official ones. Those galenicals which are known to be extremely variable in their character and action, and by their nature do not admit of exact control by chemical means, have been the subject of physiological research. Not being satisfied with the methods hitherto available, special processes of standardisation have been developed which give more complete control over the finished products. This subject is still one of continuous research.

The standards adopted have been chosen after the examination of very many different samples of drugs, and represent the average of the amounts of active principle found in preparations made from good specimens. Thus the dose remains the same as that of the older preparation, but the prescriber is certain of always obtaining the proper effect instead of one varying from time to time with the particular batch of extract of tincture used, and the advantage of this certainty, both to the reputation of the prescriber and the health of the patient, can hardly be over-estimated.

[Sidenote: Prolonged scientific research]

[Sidenote: ‘Ergotoxine’]

To attain the highest standard in these as in other preparations for medicinal use, extensive scientific research and many technical experiments have been made. Long-continued researches in the Wellcome Chemical and Physiological Research Laboratories led to the issue of ‘Hemisine,’ a physiologically standardised product which presents the active principle of the medulla of the supra-renal gland in a dry, soluble state. It is perfectly stable in all climates, and permits of the instant preparation of fresh reliable solutions possessing the characteristic hæmostatic and other properties of the supra-renal gland. Similarly, as the result of researches carried out at the Wellcome Physiological Research Laboratories, crystalline salts of a specific alkaloid, which produces the characteristic effects of ergot on the blood-pressure and the uterus, have been obtained in a state of chemical purity. To this alkaloid the scientific name “Ergotoxine” has been given. In ‘Ernutin,’ Burroughs Wellcome & Co. are enabled to present a preparation of uniform potency, containing the specific active therapeutic principles of ergot, chief of which is the alkaloid ergotoxine, in a state of purity which up to the present has never been approached. It is physiologically standardised by observation of its effects on the vaso-motor functions of the sympathetic nervous system.

[Sidenote: Aconitine]

ACONITINE as met with in commerce has been found to vary greatly in purity, and therefore in physiological effect. It is of the utmost importance that a definite strength should uniformly attach to so powerful a drug, and this is secured in the ‘Wellcome’ Brand product, which is free from pseudaconitine and japaconitine, and from the non-toxic aconine and benzaconine.

[Sidenote: Atropine Cocaine]

The alkaloid ATROPINE is, under this brand, issued free from hyoscine and hyoscyamine. COCAINE and its hydrochloride are prepared in a state of purity answering fully the most rigid tests.

[Sidenote: Aloin, Crystal]

ALOIN (CRYSTAL). This greatly improved product is barbaloin in well-defined crystals, and is free from resin.

[Sidenote: Bismuth Salicylate]

The bismuth salts have received much attention, a notable improvement being made in the quality of BISMUTH SALICYLATE. It is well known that there has been a lack of uniformity in the composition of this article, and that not infrequently preparations have been sold under this name which have consisted merely of a mixture of salicylic acid with the oxide or some salt of bismuth. ‘WELLCOME’ BRAND BISMUTH SALICYLATE is made from physiologically pure salicylic acid, and is uniform in composition.

[Sidenote: Stable and soluble]

The scale salt known as BISMUTH AND AMMONIUM CITRATE is a very unsatisfactory preparation. BISMUTH CITRATE (SOLUBLE), ‘WELLCOME’ BRAND, has the same therapeutic properties, but is much more stable in character. Being very freely soluble in water and yielding a bright solution, it is well adapted for the extemporaneous preparation of a solution corresponding to Solution of Bismuth and Ammonium Citrate, B.P., or for preparations in which the U.S.P. salt is used. Like the latter, which it is designed to supersede, it is not compatible with acid liquids.

BISMUTH AND LITHIUM CITRATE (SOLUBLE), ‘WELLCOME’ BRAND. This new combination, in the form of handsome colourless scales, is readily soluble in water. It is thus particularly convenient when the effects of both lithium and bismuth are desired, as in gouty dyspepsia.

[Sidenote: Sedative and hæmatinic]

BISMUTH AND IRON CITRATE (SOLUBLE), ‘WELLCOME’ BRAND, permits the sedative properties of the bismuth to be exerted on the digestive organs, while the iron, which is presented in a soluble, non-irritating and non-astringent condition, is readily absorbed to attack the anæmia which is the exciting cause in some cases of dyspepsia. The salt is in the form of yellowish-green scales, readily soluble in water.

[Sidenote: Definite composition]

IRON ARSENATE (SOLUBLE), ‘WELLCOME’ BRAND, differs from the insoluble amorphous powders, of indefinite composition, so often prepared under this name, in being a scale preparation readily soluble in water, and containing an amount of arsenic equivalent to 34–35 per cent. of anhydrous ferric arsenate.

[Sidenote: Soluble Manganese Salts]

A series of _soluble_ MANGANESE SALTS and combinations of the same with Arsenic, Quinine or Strychnine are unique forms in which this chemical may be prescribed with the best effect.

[Sidenote: Pilocarpine]

The ‘WELLCOME’ BRAND salts of PILOCARPINE, as a result of prolonged and costly investigations, are free from the less active isopilocarpine and the inactive pilocarpidine with which they are usually found to be associated. The melting point indicates the high purity of these salts.

[Sidenote: Quinine Sulphate]

A special feature is made of QUININE SULPHATE in the convenient form of _compact crystals_ occupying one-third the space of the bulky chemical ordinarily offered.